Biomedical subjects

H Gurling

Publications and source records attributed to H Gurling.

40 records · Page 3Linked to original sources

PubMed1985

Application of molecular biology to mental illness. Analysis of genomic DNA and brain mRNA.

Techniques in molecular biology and genetics have made it possible to systematically study gene effects in human disease. The number of gene clusters specifically encoding human brain structure and function is probably about 1,600 or half of all clusters. Evolutionary effects such as linkage disequilibrium and conservation of exons (DNA encoding structural proteins) as well as the fact that there are a tractable number of gene clusters involved, tend to make it quite likely that DNA pathology or DNA variation (polymorphism) predisposing to mental illness can be detected. Genes involved in mental illness can be detected either by studying DNA obtained from blood samples (genomic DNA) directly or by the analysis of mRNA and proteins from suitable cell or tissue preparations. The study of gene expression in the human brain is still in its infancy, nevertheless there are some hints that non-poly-adenylated mRNAs may be important in brain development and certain transcribed sequences may have a specific role in gene expression of the brain. The advantage of studying genomic DNA by the use of linkage and association analysis in multiply affected families is that it will, in the end, almost certainly yield a positive result for a disease with a substantial genetic input. Analysis of gene products from tissues such as brain could in theory detect specific disease genes but the approach will also identify genes secondarily affected by the disease process. Differentiation of genes that are primarily causing mental illness from those that are secondarily affected can be carried out by using such candidate genes as linkage markers in multiply affected families.

Animals↗

PubMedDate not supplied

Molecular genetic evidence for heterogeneity in manic depression.

Manic depression is a severe cyclic mental illness that can be unipolar or bipolar and has a lifetime risk of approximately 7 per 1,000 in most populations. Families with multiple cases of manic depression have been described that are compatible with both autosomal dominant and X-linked modes of genetic transmission. Psychoactive antidepressant and stimulant drugs that help to ameliorate depression and mania are thought to act by affecting catecholamine neurotransmitter systems such as adrenaline, noradrenaline and dopamine, amongst others. Mutations affecting the tyrosine hydroxylase (TH) gene, which encodes the rate-limiting enzyme for the synthesis of these three neurotransmitters, might therefore be responsible for causing the manic depressive phenotype. We have studied three Icelandic kindreds amongst whom it appears that a single autosomal dominant disease allele is segregating. In these families there were 44 cases amongst 73 individuals at risk. Genetic linkage studies were carried out using clones encoding tyrosine hydroxylase the variable portion of the Harvey-ras-1 (HRAS1) locus and the variable region of the insulin gene (INS). All three markers are closely linked on chromosome 11 and were used to observe the segregation of restriction fragment length polymorphisms (RFLPs) in the three affected kindreds. We found no evidence for linkage to these markers in any of the three families. In contrast, Gerhard et al. found linkage between manic depression and HRAS1 in a single large Amish kindred. We conclude that there is genetic heterogeneity of linkage in manic depression. Therefore mutations at different loci are responsible for the manic depressive phenotype in the Amish and in Iceland.

Bipolar Disorder↗

PubMedDate not supplied

A procedure for combining two-point lod scores into a summary multipoint map.

Multipoint linkage analysis can be extremely demanding in terms of computer time and memory, and these requirements rise exponentially with the number of markers used. A method is described for producing a rapid approximation to a multipoint analysis from the supplied results of two-point analyses with each marker. The method depends on regarding the lod scores as if they were obtained from a number of independent phase-known meioses, and making estimates concerning the proportion of all meioses which are likely to be informative for each marker. It then becomes possible to estimate the amount of information from each marker or pair of markers which is independent of information from other markers. The lod scores arising from independent contributions may then be summed to approximate the true multipoint lod score. The method has been implemented in a computer program called FASTMAP which is freely available. It has been tested on a variety of simulated and real data. In most circumstances it performs well, with a high correlation between the estimated and true multipoint lod score and little bias. However occasionally the results of the estimate deviate markedly from the multipoint lod score, especially at map positions very close to the markers. The overall usefulness of the method will therefore need to be further evaluated, but it does seem adequate at least for building exclusion maps and carrying out preliminary and exploratory analyses.

Bipolar Disorder↗

PubMedDate not supplied

Microsatellite polymorphisms for chromosome 5 bands q11.2-q13.3.

The genes for spinal muscular atrophy (SMA) and a possible subtype of schizophrenia (SCZD1) have been mapped to chromosome 5q11.2-q13.3. DNA markers have been mapped to 5q11.2-q13.3 using a hybrid cell line deleted for this region [Gilliam et al., Genomics 1989;5:940-944]. Genomic lambda clones for these markers facilitated the identification of highly polymorphic microsatellites. A total of ten microsatellites were identified and sequenced. Of these, seven were found to be polymorphic. Four had polymorphism information content values > 0.7. New polymorphic microsatellites were sequenced for D5S76, D5S125, D5S39, D5S127 and HEX-B. Two-point and multipoint analysis in non-CEPH pedigrees confirmed that the microsatellites were in tight linkage with each other. These new microsatellites will increase the efficiency of linkage analysis for these disorders.

Alleles↗